Type 1 diabetes is an autoimmune disease that can arise due to a failure to develop immunological tolerance to self-antigens present in the pancreas. In NOD mice, which develop type 1 diabetes due to a thymic defect in central tolerance, alpha/beta T cells are produced that attack the pancreas and render it unable to produce insulin. Various methods of inducing peripheral immune tolerance to critical self-antigens can delay or decrease the severity of type 1 diabetes. A major self-antigen in both human and NOD mouse diabetes is insulin, and we recently discovered that gamma/delta T cells respond to the same insulin peptide that is recognized by many diabetogenic alpha/beta T cells, which is generated naturally in the NOD pancreas. Because studies on diabetes patients suggested that gamma/delta T cells may be an important factor in the development of the disease, and because three different studies with NOD background mice have now shown that gamma/delta T cells can suppress the development of type 1 diabetes, these findings together make a compelling argument for the further study of how gamma/delta T cells affect this disease. We have now generated NOD mice incapable of producing gamma/delta T cells, NOD.TCRdelta-/- mice, and in this project will use these mice to test the hypothesis that gamma/delta T cells which prevent or reduce type 1 diabetes represent a distinct subset that alters the response of autoaggressive alpha/beta T cells. First, we will test NOD.TCRdelta-/- mice to ascertain whether gamma/delta T cells in fact can slow or reduce the severity of type 1 diabetes in the spontaneous NOD model. Second, because different gamma/delta T cell subsets often have distinct functions, we will determine whether all gamma/delta T cells, or only a certain type, can protect against diabetes, using a NOD/SCID adoptive transfer model. We will also investigate the role of certain cytokine candidates produced by the relevant gamma/delta T cells, towards elucidating how this protection is mediated. PUBLIC HEALTH RELEVANCE: Several publications have suggested that a relatively rare T cell type, known as the gamma/delta T cell, is important in determining whether or not type 1diabetes develops. These cells were shown in some experimental models to play a suppressive role in type 1 diabetes, but it is not yet clear whether they are also able do so during normal development of the disease. The purpose of this study is to determine whether these gamma/delta T cells affect the incidence or severity of disease in spontaneously developing mouse type 1diabetes, and to determine the characteristics of the suppressive gamma/delta T cells. This work could lead to new methods of slowing or preventing type 1 diabetes, via the stimulation of suppressive gamma/delta T cells.